OBJECTIVE: To determine the impact of a nurse-led multi-disciplinary team on management of elderly patients with functional problems admitted to an acute medical admission unit. DESIGN: Data collection from the first 16 months of the team's operation. SETTING: A district general hospital, Scotland. SUBJECTS: All elderly patients with functional problems who were considered fit for immediate multi-disciplinary assessment. RESULTS: Over 1000 patients were assessed during the first 16 months. Twenty four per cent of these frail individuals were discharged directly home, of whom, almost half had some form of ongoing support. The remaining 76% were transferred for ongoing care to other wards in the Medical Directorate. Of this group, 49% moved to general medicine, 43% to geriatric assessment and 8% to the Stroke Unit. The team were perceived to improve the appropriateness of these transfers by enabling staff to review both the medical and functional needs of elderly patients when deciding on the best setting for ongoing care. CONCLUSIONS: Immediate multi-disciplinary assessment of elderly patients admitted to a medical admissions unit enables the early supported discharge of a proportion of elderly and enhances the ability of the hospital to place appropriately those patients requiring a longer stay.

Acute Disease↗

PubMed1999

Training opinion leaders to improve physician practice in the management of dyslipidemia.

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Canada↗

PubMed1999

Intensely cytotoxic anthracycline prodrugs: galactosides.

We have reported the synthesis of a series of anthracycline analog prodrugs that give rise to intensely cytotoxic metabolites in the presence of carboxylate esterases and beta-glucuronidases. We now report structurally related prodrugs that are converted to similar potent metabolites in the presence of beta-galactosidases. The prototypical compound, N-[(4"RS)-4"-ethoxy-4"(1'"-O-beta-D-galactopyranosyl)butyl]daunorubicin, 8a, was prepared by reductive condensation of daunomycin with 1-O-[(1'RS)-1'-ethoxy-4'-oxobutyl]-2, 3, 4, 6-tetra-O-acetyl-beta-D-galactopyranoside in the presence of sodium cyanoborohydride, followed by deacetylation of the galactoside moiety with sodium methoxide. A related prodrug (8b) with enhanced lipophilicity (the 4'-hexoxy analog of 8a) and 8c (the propyldaunomycin analog of 8a) were prepared for comparative studies. 8a and 8b were isolated after chromatography on silica as a mixture of 4'R and 4'S diastereomers; 8c, on the other hand, was resolved into its component 3' diastereomers, 8c(R) and 8c(S). 8a, 8c(R) and 8c(S) showed no evidence of decomposition when incubated at 37 degrees C in 0.05 M phosphate buffer, pH 7.4, for 2 weeks; 8b, under the same conditions, was degraded with a half-life of 49 h. In the presence of two units of Escherichia coli beta-galactosidase per pmol of substrate, the half-lives of 8a, 8b, 8c(R) and 8c(S) were 1.98, 1.06, 3.5 and 2.4 h, respectively. HPLC analysis of the incubation mixtures showed that 8a and 8b gave rise to a single, chromatographically identical metabolite. 8c(R) and 8c(S) also gave rise to a single, identical metabolite. 8a and 8b were nearly one million-fold more toxic to human A375 melanoma cells in culture in the presence of E. coli beta-galactosidase than in the absence of the enzyme. The activation products of 8c(R) and 8c(S) were approximately 1000-fold less potent. These beta-galactoside prodrugs have chemotherapeutic potential for use in conjunction with tissue-targeting strategies such as antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT).

Antibiotics, Antineoplastic↗

PubMed1998

Intensely potent doxorubicin analogues: structure-activity relationship.

N-(5,5-Diacetoxypent-1-yl)doxorubicin (1b) is an intensely cytotoxic doxorubicin analogue that retains full potency against tumor cells that express elevated levels of P-glycoprotein and are resistant to doxorubicin. 1b was designed to be hydrolyzed in the presence of carboxylate esterases to N-(5-oxypent-1-yl)doxorubicin, an aldehyde capable of existing in equilibrium with a cyclic carbinolamine. To investigate the structural determinants of potency for 1b, we have prepared a series of chemically related compounds in which various omega-[bis(acetoxy)]alkyl or omega-[bis(acetoxy)]alkoxyalkyl groups are substituted at the 3'-amino position of the daunosamine sugar. These groups were selected to assess the effect of chain length, oxygen substitution, and carbinolamine ring size on analogue potency. The compounds were evaluated for their ability to inhibit the in vitro growth of the following cell lines: (a) Chinese hamster ovary (CHO) cells, (b) a CHO cell mutant 100-fold resistant to doxorubicin that expresses elevated levels of P-glycoprotein, (c) a murine ductal cell pancreatic adenocarcinoma (Panc 02), and (d) a murine mammary carcinoma (CA 755). The most potent members of the series were those that could form a straight chain aldehyde intermediate after esterase-mediated hydrolysis of the omega-bis(acetoxy) groups and give rise to 5- or 6-membered ring carbinolamines. Analogues capable of forming 7-, 8-, or 9-membered carbinolamines were markedly less active. The N-methyl derivative of 1b, which cannot give rise to a cyclic carbinolamine, was 2 orders of magnitude less potent than 1b. A branched chain analogue, 1f, which contained a tertiary carbon atom adjacent to the omega-bis(acetoxy) groups, was also substantially less active than its nonbranched counterpart, 1a. These findings suggest that the chain length of the 3'-amino substituents and the ability of the derived aldehydes to form 5- or 6-membered carbinolamines are critical determinants of biologic potency.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Intensely cytotoxic anthracycline prodrugs: glucuronides.

We previously reported the synthesis of a series of doxorubicin analogue prodrugs that give rise to intensely cytotoxic metabolites in the presence of carboxylate esterases. We now report studies on structurally related beta-glucuronide prodrugs that are converted to similar potent metabolites in the presence of beta-glucuronidases. These prodrugs were prepared by reductive condensation of daunomycin or doxorubicin with methyl 1-O-[(1'RS)-1'-ethoxy-4'-oxobutyl]-2,3,4-tri-O-acetyl-beta-D- glucopyranosyluronate in the presence of sodium cyanoborohydride followed by base-mediated cleavage of the glucuronate protective groups. The doxorubicin derivatives were isolated in very low yield, most likely because of the inherent base lability of the parent aglycone. By contrast, fairly good yields of the more base-stable daunomycin analogues were obtained. The target daunomycin glucuronide, N-[(4"RS)-4"-ethoxy-4"-(sodium 1"'-O-beta-D-glucopyranuronate)butyl]daunorubicin (6a), had a half-life of 30 h when incubated at a concentration of 12 microM in aqueous 0.05 M phosphate buffer, pH 7.4, at 37 degrees C. Under identical conditions in the presence of 197 units/mumol of Escherichia coli beta-glucuronidase, 6a was hydrolyzed with a half-life of 1.7 h. The single metabolite observed was chromatographically identical with that formed from the hydrolysis of N-(4,4-diacetoxybut-1-yl)daunomycin by carboxylate esterases. 6a was approximately 10,000-fold more toxic to human A375 melanoma cells in the presence of E. coli beta-glucuronidase than in the absence of the enzyme. These findings indicate the therapeutic potential of anthracycline glucuronide prodrugs as independent entities or four use in conjunction with enzyme tissue-targeting strategies such as antibody-directed enzyme prodrug therapy (ADEPT) or gene-directed enzyme prodrug therapy (GDEPT).

Antibiotics, Antineoplastic↗

PubMed1997

Mutagenic consequences of the incorporation of 6-thioguanine into DNA.

6-Thioguanine (S6G) has been used in the treatment of acute leukemias because of its cytotoxic effect on proliferating leukemic cells. The cytotoxicity of S6G is thought to derive from its incorporation into DNA in place of guanine. The deoxyribonucleoside triphosphate of S6G, SdGTP, is a good substrate for bacterial and human DNA polymerases (Ling et al., Mol Pharmacol 40: 508-514, 1991). Since SdGTP was observed to misincorporate in place of adenine at a greater frequency than did dGTP, it appeared plausible that this analog could produce more subtle effects (mutations) due to mispairing with thymine. To assess whether such mutations occur, SdGTP was incorporated into the lacI gene of phage M13lacISaXb in reactions that omitted dGTP (-G) or dATP (-A). LacI mutation frequency was determined by beta-galactosidase colorimetric staining (inactivation of the lac repressor results in blue plaques in the absence of inducer). When a high concentration of SdGTP (24 microM) was used in the DNA polymerase reaction, phage infectivity was inhibited. When a relatively low concentration (2.4 nM) was added to the -G and -A reactions, mutagenic effects were observed. DNA sequencing of mutant progeny arising from the -G + S6G reaction revealed C-to-T base transitions and some C-to-A transversions. Similarly, the presence of SdGTP in the -A reactions led to mutants with T-to-C transitions. No insertions or deletions were observed. These data indicate that mispairing of S6G with thymine leads to mutagenic effects in this assay.

Bacterial Proteins↗

PubMed1995

Biochemical pharmacology of penclomedine (NSC-338720).

Penclomedine (PEN) is a synthetic pyridine derivative that has been selected for clinical development based on its activity against human and mouse breast tumors implanted in mice. Its mechanism of action was unclear, and we were interested in determining its mechanism of cytotoxicity in vitro and in vivo. We found chromosome breaks, gaps, and exchanges in P388 ascites cells from BD2F1 mice treated with 200 mg/kg PEN. Maximal observed damage occurred 24 hr after drug administration. Alkaline elution indicated only limited DNA strand breaks and interstrand cross-linking. In vitro, PEN (75 micrograms/mL) inhibited RNA and DNA syntheses almost completely. In addition, incubation of [14C]PEN with rat liver S-9 fraction in the presence of calf thymus DNA resulted in the stable transfer of radioactivity to DNA. Addition of butylated hydroxytoluene, a free radical scavenger, to the incubation mixture inhibited the binding of drug to DNA, implicating free radicals as the ultimate reactive species. These data suggest that PEN can be metabolized to free radical, DNA-reactive products, and that its cytotoxicity is due to chromosomal damage produced by monofunctional alkylation. As an alternate mechanism, the ability of PEN to inhibit cellular dihydroorotate dehydrogenase was explored. Although PEN is an inhibitor of this enzyme in cells in vivo, in vitro, and in isolated cell sonicates, HPLC analyses of ribonucleotide triphosphate pools in P388 cells showed that all triphosphates had increased, especially UTP. Addition of uridine to the cell culture failed to prevent PEN-mediated cytotoxicity, suggesting that inhibition of de novo pyrimidine biosynthesis was not likely to be an important mechanism of action of this drug. These data suggest that PEN is activated in cells to a free radical that binds DNA.

Animals↗

PubMed1995

5'-[4-(Pivaloyloxy)-1,3,2-dioxaphosphorinan-2-yl]-2'-deoxy-5-fluorouridine: a membrane-permeating prodrug of 5-fluoro-2'-deoxyuridylic acid (FdUMP).

5'-[4-(Pivaloyloxy)-1,3,2-dioxaphosphorinan-2-yl]-2'-deoxy-5 -fluorouridine (1c) was designed as a potential membrane-permeable prodrug of 2'-deoxy-5-fluorouridine 5'-monophosphate (FdUMP), a putative active metabolite of the antitumor drug 5-fluorouracil (FU). It was anticipated that 1c would be hydrolyzed in vivo by carboxylate esterase (E.C. 3.1.1.1) to the labile 4-hydroxy analogue 2a, which should penetrate cells by passive diffusion and ring open to the aldehyde 3a. Spontaneous elimination of acrolein from 3a would then generate the free nucleotide, FdUMP. 1c might also penetrate cells directly and undergo the same degradation sequence after hydrolysis by cellular esterases. 1c was prepared by condensing 2-hydroxy-2-oxo-4-(pivaloyloxy)-1,3,2-dioxaphosphorinane with 2'-deoxy-5-fluorouridine (FUdR) in the presence of triphenylphosphine and diethyl azodicarboxylate. 1c was moderately stable in aqueous buffers over the pH range 1-7.4 (T1/2 > 30 h). In the presence of carboxylate esterase, however, it was degraded, in a concentration-dependent manner, to FdUMP. No intermediates were detected in the incubation mixture. In mouse plasma, 1c was degraded first to FdUMP and then to FUdR. The latter is presumably formed by dephosphorylation of FdUMP by plasma 5'-nucleotidases or phosphatases. 1c and FU inhibited the growth of Chinese hamster ovary (CHO) cells in culture at a concentration of 5 x 10(-6) M. 1c was equally potent against a CHO variant that was 20-fold resistant to FU. Administered intraperitoneally for 5 consecutive days, 1c was as effective as FU at prolonging the life span of mice bearing P-388 leukemia. In the presence of 2-mercaptoehtanesulfonic acid, an acrolein scavenger, 1c was equally effective against a P-388 mutant cell line that was resistant to FU. Collectively, these data suggest that 1c acts as a membrane-permeable prodrug of FdUMP. This prodrug strategy may be generally useful for introducing dianionic phosphates and phosphonates into cells.

Animals↗

PubMed1995

Mechanisms of cyclophosphamide resistance in a human myeloid leukemia cell line.

The 4-hydroperoxycyclophosphamide (4HC)-resistant B5-180(3) subline of the cloned KBM-7/B5 cell line was developed as a model of induced cyclophosphamide resistance in human myeloid leukemia. Based on IC90 values, this subline was approximately 20-fold resistant to 4HC. Furthermore, it was significantly cross-resistant to phosphorodiamidic mustard (PM), whose cytotoxicity is independent of aldehyde dehydrogenase (ADH). Using alkaline elution we found that the resistant line had decreased initial levels of DNA interstrand cross-links (ISCs) following 4HC but not PM treatment. The resistant cells also appeared to remove ISCs from their DNA more rapidly than the parental cells. Our data therefore suggest that 4HC resistance in the B5-180(3) subline is multifactorial; ADH is an important mediator of its resistance to ISC induction by 4HC, while a second process, which may involve an increased ability to tolerate drug-induced DNA damage, appears to be important for its resistance to both 4HC and PM. The B5-180(3) cells were also cross-resistant to gamma-radiation (approximately 1.7-fold at a surviving fraction of 0.1); if generally applicable, such effects could have important clinical implications, since pretransplant total body irradiation is a major component of the eradication of leukemic cells.

Aldehyde Dehydrogenase↗